Regulatory role of hypothalamic AMP-kinase in body energy metabolism

AMP激酶（AMPK）是调节能量代谢的代谢传感器。我们以前已经表明，瘦素刺激脂肪酸氧化骨骼肌通过AMPK。AMPK广泛表达，表达部位包括神经元和神经胶质细胞。我们推测下丘脑AMPK可能介导激素和营养对摄食和能量平衡的影响，包括瘦素在内的许多促食欲素抑制小鼠下丘脑弓状核和室旁核α2 AMPK活性，而包括AGRP在内的许多食欲素则增加下丘脑核α2 AMPK活性。下丘脑内侧区组成性激活（CA）-AMPK和显性负性（DN）-AMPK的表达调节摄食量和体重，下丘脑内侧区CA-AMPK抑制瘦素诱导的厌食。此外，PVH中CA-AMPK的慢性表达也增加了食物摄入，从而导致大量肥胖。我们使用C2 C12细胞进一步研究了瘦素诱导骨骼肌细胞脂肪酸氧化的分子机制。瘦素刺激C2 C12细胞脂肪酸氧化和α 2 AMPK活性。瘦素诱导的脂肪酸氧化被α2 AMPK的siRNA消除。此外，我们发现α2β2γ1 AMPK易位到细胞核并刺激PPARa基因表达以响应瘦素，而α2β1γ 1 AMPK保留在细胞质中并磷酸化乙酰辅酶A羧化酶，在那里它诱导线粒体中的脂肪酸氧化。我们的研究发现α2β2γ1AMPK的核转位是由α 2亚基的核定位信号介导的，β1的豆蔻酰化使α 2 AMPK保留在线粒体膜上，并刺激脂肪酸氧化。因此，瘦素-AMPK系统在控制食物摄入和脂肪酸代谢中起着至关重要的作用。

AMP kinase (AMPK) is a metabolic sensor that regulates energy metabolism. We have previously shown that leptin stimulates fatty acid oxidation in skeletal muscle via AMPK. AMPK is widely expressed-locations include neurons and glial cells. We hypothesized that hypothalamic AMPK might mediate hormonal and nutrient effects on food intake and energy balance.Many anorexigens including leptin suppressed α2 AMPK activity in the arcuate (ARH) and paraventricular (PVH) hypothalamus in mice, while many orexigens including AGRP increased α2 AMPK activity in the hypothalamic nucleus. Expression of constitutively active (CA)-AMPK and dominant negative (DN)-AMPK in the medial hypothalamus reciprocally regulated food intake and body weight, and CA-AMPK in the medial hypothalamus inhibited leptin-induced anorexia. Moreover, chronic expression of CA-AMPK in the PVH also increased food intake, then causing massive obesity.We further examined the molecular mechanism of leptin-induced fatty acid oxidation in skeletal muscle cells, using C2C12 cells. Leptin stimulated fatty acid oxidation and a2 AMPK activity in C2C12 cells. Leptin-induced fatty acid oxidation is abolished by siRNA of α2 AMPK. Furthermore, we found that α2β2γ1 AMPK translocated to the nucleus and stimulated PPARa gene expression in response to leptin, while α2β1γ1AMPK retained in the cytoplasm and phosphorylated acetyl-CoA carboxylase, where it induced fatty acid oxidation in mitochondria. Our studies identified that nuclear translocation of α2β2γ1AMPK is mediated by the nuclear localization signal in the a2 subunit, and myristoylation of β1 retains the a2AMPK to the mitochondrial membrane and stimulates fatty acid oxidation. Thus, leptin-AMPK system plays a crucial role in the control of food intake and fatty acid metabolism.